Roland Tisch

Roland Tisch

Area of interest

The work ongoing in the laboratory focuses on three general areas. The first entails investigation of mechanisms regulating autoimmune recognition and responses to self-proteins. For this purpose we employ a murine model of Type 1 diabetes (T1D) that is characterized by the T cell mediated destruction of the insulin producing beta cells found in pancreatic islets. A broad range of aspects regarding the disease process are being studied, including the development and immunoregulation of beta cell-specific CD4+ and CD8+ T cells, biochemical interactions between T cell receptors and MHC molecules, and the regulation of dendritic cell and macrophage activation and effector function. A significant effort is also being made towards the development of "vaccines" to prevent and/or treat T1D. Approaches include the use of soluble MHC class I molecules and genetic vaccines to selectively target beta cell-specific T cells.

Our work investigating the immunoregulation of autoimmunity provides the foundation for the second major area of interest for the laboratory, that being cancer immunotherapy. In contrast to the treatment of autoimmunity, the goal of cancer immunotherapy is to induce immune reactivity to self-proteins. Our emphasis is the development of genetic vaccines encoding tumor antigens and a variety of cytokines to promote a robust tumor-specific CD4+ and CD8+ T cell response. Currently, murine models of breast and pancreatic cancer are being employed to study the in vivo efficacy of genetic vaccines encoding HER2/neu and mucin-1, respectively. Two strategies of genetic vaccination, each with distinct advantages, have largely been studied. The first, entails the use of an alphavirus Venezuelan equine encephalitis virus (VEE)-replicon system which has several features well suited for genetic vaccination. The most salient of these features, however, is the ability of VEE-replicons to selectively infect dendritic cells in vivo. Dendritic cells are characterized in part by an exceptional capacity to initiate and establish potent T cell immunity. Our second strategy is to employ plasmid DNA (pDNA) vaccines, which we and others have shown to be effective in inducing persistent T cell and antibody responses in a variety of model systems. Studies are currently being initiated to assess a third strategy of genetic vaccination based on the application of adeno-associated viral recombinants.

The third area of study focuses on signaling events which regulate the activation and effector function of dendritic cells (and macrophages). Specific interest is in the transcription factor NF-kappaB, which regulates the expression of genes critical for dendritic cell development and maturation.

In summary, the work ongoing in the laboratory encompasses both fundamental and applied aspects of immune recognition of self-proteins in the context of autoimmunity and cancer, in addition to defining key events which regulate dendritic cell maturation and effector function.